Adult cardiomyocytes have limited ability to undergo hyperplasia in response to cardiac injury. Recent studies have suggested that bone marrow-derived stem cells (BMC) may undergo differentiation into cardiomyocytes. Despite the initial promise of these exciting results and their potential therapeutic application, many questions remain and much controversy exists over the ability of stem cells to transdifferentiate into functional cardiomyocytes. This Collaborative Application proposes a multi-disciplinary approach to investigate bone marrow-derived stem cell survival and cardiomyogenic differentiation in ischemic myocardium. The overall application is based on three working hypotheses First, that specific subpopulations of bone marrow-derived stem cells can differentiate to functional cardiomyocytes, second, that genetic modification of bone marrow-derived stem cells can promote cell engraftment, cardiomyogenic differentiation, and contractile function following cell implantation, and third, that bone marrow-derived stem cells can decrease deleterious ventricular remodeling and directly contribute to contractile performance in post-myocardial infarcted hearts. To test these hypotheses, we have assembled a team of investigators with complementary expertise in small animal and large animal models of cardiac injury, as well as cellular physiology, signal transduction pathways, stem cell biology, and molecular virology. Understanding the specific signaling pathways that control bone marrow stem cell survival in ischemic myocardial infarction, developing approaches to local modulation of these pathways, and evaluating their functional contribution to the progression of heart failure are the ultimate goals of this Collaborative RO1. We believe that these goals coincide with the stated objectives of the RFA and that the interdisciplinary effort proposed can successfully meet these objectives. In this way, we hope to contribute to an improved understanding of the pathophysiology of heart failure and ultimately, the development of novel therapeutic strategies.